PATHOLOGY OF ALCOHOL DEPENDENCE

1. AETIOPATHOLOGY OF ALCHOLISM Dr Sushil Kumar S V MB BS, MD (psychiatry), MHA, FIPS Consultant Neuropsychiatrist

2. Alcohol misuse is a bio-psychosocial phenomenon it results from the contribution of multiple individual and environmental risk factors. Causal mechanisms have been proposed by researchers in fields as diverse as social sciences, behavioral psychology, psychopathology, genetics, pharmacology, toxicology, and neurobiology.

3. Two very different schools of thought attract to the current notions of alcoholism the social learning MODEL It contends that alcohol misuse is an acquired behavior which the individual is capable of correcting with adequate cognitive–behavioral training; even to the point of relearning to drink in a ‘controlled' manner. THE DRAWABACKS OF the learning model tends to play down the importance of predisposing factors, and to ignore the variance in individual biological responses to alcohol, or the brain changes caused by chronic intoxication. it assumes that all alcoholics are basically the same and that they are not different from any other drinker in their capacity to exert control over alcohol use.

4. The disease models of alcoholism the inability to restrict the quantity or frequency of drinking is a key notion in the disease or ‘medical' model of alcoholism. This anomaly is thought to result from heavy alcohol exposure, or else to pre-exist in constitutionally vulnerable individuals. This model further suggests that, once in place, such loss of control over drinking is irreversible. Pioneer medical authors such as T. Trotter in the early 1800s, Magnus Huss, who coined the term alcoholism in 1849-had already maintained that the disorder involves the loss of voluntary control over drinking and this is still the opinion of the scientific community today

5. According to ideologists AND M oralists who opposed that notion because it exempts the drinker from personal blame. they viewed any form of drinking as intrinsically wrong, and alcohol itself as an evil which should be eliminated through prohibition. They maintained alcoholics are always capable of choosing whether or not to drink, and must assume full responsibility for their behavior. Thus denying the existence of a pathological process

6. Sociocultural factors the prevalence of alcohol problems varies markedly across different cultural and social settings; that certain environmental conditions appear to facilitate their occurrence while others seem to prevent them Macrocultural influences such as values, beliefs, and mores; social role functions; local economy; customs and dietary habits; rapid social change; and cultural stress do shape and dictate the way alcohol is used in societies.

7. Occupation and alcohol the risk of hospital admission for alcoholic psychosis, acute intoxication, and liver cirrhosis is elevated in unskilled and blue collar workers when compared with higher occupational categories alcoholics are over-represented in occupations with flexible work schedules, in those less supervised, and in the ones which facilitate access to alcohol frequency of heavy drinking (i.e. episodes of intoxication, 5+ drinks at a time) is inversely correlated with age, income, and level of education

8. Sociocultural Risk Factors Male role Lower education Lower income Marital breakdown Certain occupations Idleness Cultural ambivalence towards drinking Social stress

9. Individual vulnerability Genetic influences The most powerful predictor of alcohol misuse in any individual is the occurrence of alcoholism in first-degree relatives. Men and women belonging to families with alcoholic parents and/or siblings are twice as likely to develop the disorder than those without such family history. The risk is threefold when the disorder is present also in second- or third-degree The excess probability observed within single family groups suggests that alcohol misuse could be a genetically transmitted behavior

10. Twin studies The comparison of concordance rates for alcoholism in monozygotic and dizygotic twins permits to test the genetic basis of the disorder. Using general population prevalence rates as reference, to have an alcoholic monozygotic sibling markedly increases the chances of developing alcoholism Dizygotic co-twins of alcoholics also present elevated risk ratios, but to a lesser degree. it must be noted that between 40 and 70 per cent of the identical co-twins of alcoholics do not present the disorder, and that such variance can only be due to non-genetic causes.

11. Adoption studies The study of adopted-away children of alcoholic parents is a powerful approach to the elucidation of the nature of the family transmission of alcoholism. A genetic vulnerability, of course, should express itself even when such children are brought up by non-alcoholic adoptive parents. All adoption studies consistently report an increased risk in these offspring, regardless of the family environment where they grow up. The probability of occurrence in the probands is much higher than in the control adoptees. This was demonstrated with Danish (risk ratio 3.6), Swedish (risk ratio 1.3), and American (risk ratios 3.5 and 3.6)

12. The offspring of alcoholic parents are exposed to an excess risk. A more detailed analysis of the adoption data shows that the biological parents of alcoholic adoptees, when compared to the controls, are not only more likely to present alcoholism but also antisocial behaviour. Antisocial personality is also significantly more prevalent in alcohol-abusing adoptees than in controls. The evidence indicates that the alcoholism–antisocial personality tandem is much more ‘inheritable' than alcoholism alone. In decreasing order of significance, alcohol abuse in adoptees is predicted by their own antisocial personality, biological parents' alcoholism, biological parent's antisocial history, and, to a much lesser degree, history of alcoholism or psychopathology in the adoptive parents.

13. Biological predisposition Alcohol sensitivity Compared to controls, a significantly larger percentage of men with family history of alcoholism present a lesser physiological response to alcohol; in terms of both subjective sensations and objective measurements ( postconsumption plasma cortisol levels). A lower sensitivity is assumed to lead to heavier drinking and predicts the eventual development of alcoholism. the ‘innate' low response to alcohol is an independent risk factor, regardless of family history. men with multigenerational family history of alcoholism tend to derive a greater anxiolytic effect from alcohol. Such increased effects can be expected to reinforce heavy drinking.

14. Biochemical markers On average, alcoholics have lower than normal levels of platelet serotonin and of its metabolite 5-hydroxyindole acetic acid in cerebrospinal fluid; especially the problem drinkers who exhibit impulsive and violent behaviour. This serotonin deficiency profile was also found to be abnormally prevalent in young adults with a family history of alcoholism. The monoamine oxidase enzyme is of interest because it participates in the breakdown of neurotransmitters which are involved in the brain action of alcohol. Abnormally low levels of monoamine oxidase platelet activity were found to be linked to a family history of alcoholism, as well as to an earlier age of onset and a higher severity of the disorder. Both these biochemical deviations seem to be more significant among male than female subjects, and to be strongly associated with antisocial behaviour.

15. Neurophysiology Event-related potentials Alcoholics have been found to present a lower than normal amplitude of the P300 wave, when such brain potential is evoked through complex visuomotor tasks. The P300 potential is thought to measure attentional and memory processes, and its amplitude tends to increase with age and neurological maturity. low P300 amplitude could be observed also in young offspring of alcoholics, both male and female, who had not yet started drinking. It is consequently suggested that such neurophysiological finding might be a biological marker of biological vulnerability to alcoholism. However, P300 anomalies are not specific to alcoholism and are observed also in other psychiatric disorders.

16. Molecular genetics a variant (Taql-A1 allele) of the human dopamine receptor gene DRD2 was more prevalent in alcoholics than in controls (linkage disequilibrium), and that this allele could be a marker for heightened responsiveness to pharmacological stimulation (i.e. increased baseline positive reinforcement). However, such genetic variance exists across ethnic groups, and that it is not even a consistent finding in all samples of alcoholics. There is little doubt that alcohol abuse will be found to be a polygenic disorder. The first genome-wide screens for alcoholism in humans have produced evidence of several chromosomal regions linked to alcohol dependence. A conclusive finding so far is a ‘protective' locus near the alcohol dehydrogenase gene cluster in chromosome 4. “ Alcohol Dependence” Phenotype ( chr 1&4) “Low Level of Response” Phenotype( chr 1) “Alcoholism or Depression” Phenotype ( chr 1) “Unaffected” Phenotype ( chr 4 near ADH gene) “Maximum Number of Drinks” Phenotype ( chr 4) Ethanol and acetaldehyde metabolizing enzymes, of course, are known to vary across different ethnic populations, and such heterogeneity is assumed to play a role in the cross-ethnic variance of alcoholism prevalence the linkage analysis of severe alcohol dependence has identified a locus on chromosome 16, near the marker D16S675.

17. Psychological factors Personality alcoholics do not present a homogeneous premorbid personality profile. However, some distinctive trait clusters have been identified which seem to characterize different types of alcoholics. One such group (type 1) tend to score low in novelty seeking and high in harm avoidance and reward dependence. Another group (type 2) is formed by the natural thrill seekers, who appear to ignore harmful consequences and punitive responses. This latter cluster, which prevails mostly in males with early-onset alcoholism, is also typical of antisocial personalities. Of all personality features, conduct disorder and antisocial behaviour are the strongest predictors of alcohol misuse. However, more than half the alcoholic population do not have such a personality background, presenting rather with a non-specific mixture of the different personality types described in clusters A, B, and C of the DSM-IV classification.

18. Type II For early onset dependence Polysubstance abuse. Externalizing symptoms Family history positive Type I Late onset dependence. Slowly developing Family history negative

19. Psychodynamic processes early psychodynamic writings viewed alcoholism and other addictions as regressive behaviours caused by unconscious conflicts about libidinal pleasures, homosexuality, and aggression. More recent formulations emphasize ego and self-developmental problems, and consider psychoactive substance abuse as a response to psychological suffering; an attempt at reestablishing homeostasis. This is known as the self-medication hypothesis of addictions,( according to which, persons with self-regulatory deficiencies in the areas of self-care, self-esteem, self-object relations, and affect tolerance, would drink to palliate their distress.

20. Learning alcohol abuse as a behavioural pattern which has been learned through mechanisms of classical (i.e. Pavlovian) and operant conditioning According to this interpretation, the perpetuation of heavy drinking results from its association with conditioned stimuli (cues), and from the action of positive (pleasant effects) or negative (stress reduction) behavioural reinforcement. Additional components of this equation are the so-called alcohol ‘expectancies'. Alcohol abusers tend to overemphasize the pleasant aspects of drinking and to exclude the negative ones; the learning theory of alcoholism assumes that such a cognitive set is also acquired through social exposure.

21. Psychiatric comorbidity the presence of other psychiatric disorders as one of the most significant psychological risk factors in alcoholism.   The risk is particularly high in persons with schizophrenia, bipolar disorder, major depression, social phobia, panic disorder, post-traumatic stress, attention-deficit hyperactivity disorder, and antisocial and borderline personality disorders. A large proportion of the disorders diagnosed are alcohol induced and tend to dissipate in conditions of abstinence. most of the excess psychopathology observed in alcoholics is secondary to alcoholism rather than a pre-existing risk factor. It has also been suggested that the coexistence of alcoholism with other psychiatric illnesses (e.g. affective disorders) does not necessarily mean that one is causing the other, but rather that they both result from a common genetic influence.

22. Brain dysfunction Altered neuropsychological function can be seen as an additional risk factor in alcoholism minimal brain damage, attention deficit, learning disabilities, head injuries, fetal alcohol effects, or the actions of other drugs of abuse are examples of brain conditions likely to increase individual vulnerability. a transketolase deficiency (possibly genetic), which affects carbohydrate metabolism in the brain, is believed to predispose towards the occurrence of alcoholic organic brain complications

23. Neuropharmacological and neuroadaptive mechanism within specific circuits that mediate transition b/w occasional use to dependence Positive and negative reinforcement characteristics of alcohol dependence Substance dependence has aspects of both impulsivity and compulsivity at different stage of addiction cycle Impulse control disorders are characterized by an increasing tension or arousal before committing an impulsive act, feelings of pleasure, gratification or relief at time of committing act and possible regret ,self reproach or guilt following act And compulsive disorders are characterized by anxiety and stress before committing a compulsive repetitive behavior and relief from stress by performing the act As an individual moves from an impulsive to a compulsive disorder there is shift from positive to negative reinforcement driving the motivated behavior, drug addiction is a disorder that progresses from impulsivity to compulsivity in a collapse cycle of addiction

24. HOW DOES INTIATION OCCUR? PEER PRESSURE! MISCONCEPTIONS/MYTHS IMITATION/MODELLING CURIOSITY!

25. Addiction cycle has 3 stages 1.binge or intoxication 2.withdrawal/negative affect 3.preoccupation /anticipation (craving) Binge /intoxication stage have been well established from positive reinforcing effects of alcohol This involves elements of mesolimbic dopamine system {ventral tegmental area (VTA} dopamine projection to the nucleus accumbens ( NAc ) and dopamine –dependent interactions in the extended amygdala,bed nucleus of stria terminalis and shell of NAc . this system links the prelimbic cortex to the classical reward systems of the lateral hypothalamus, possibly via a descending component of the medial forebrain bundle. Effects of alcohol including its rewarding, anxiolytic or tension reducing effects may be mediated by this circuitry

26. GABA also plays role in reinforcement and GABA antagonist is known to antagonize the effects of alcohol Both glutamate and serotonin have been implicated in acute reinforcing effects of alcohol- glutamate / NMDA receptor antagonists have been shown to substitute for alcohol , in addition 5-HT3 receptor antagonists block alcohol self administration In the withdrawal /negative affect stage of addiction cycle the negative reinforcement leading to development of dependence and the vulnerability to relapse has been said to be due to counterproductive neurochemical events normally used to maintain emotional homeostasis In acute withdrawal –there is a compromised brain reward system –with increase in brain reward threshold accompanied by decrease GABAenrgic,opioid peptidergic, dopaminergic , sertonergic and glutamatergic function, as well as recruitment of brain stress systems such as corticotrophin-releasing factor (CRF)

27. It is suggested that GABAenrgic system is hypo functional during acute withdrawal The glutamate system also undergoes changes suggested by Acamprosate ,a partial modulator of brain glutamate receptors decreasing excessive drinking associated with dependence and abstinence The dopaminergic function is compromised in withdrawal –there is decrease in extracellular levels of dopamine in NAc and decrease in firing in VTA Thus GABA,glutamate and dopamine system show a neuroplasticty durin g development of dependence that has motivational consequences

28. Another major contribution to the aversive state associated with increases in brain reward thresholds during acute withdrawal has been hypothesized to be dysregulation of the brain CRF stress system. CRF present throughout brain, more in cell bodies in periventricular nucleus of the hypothalamus,the basal forebrain(notably the extended amygdala) and brain stem. CRF not only controls HPA axis response to stress but also behavioral response to it via extended amygdale CRF itself has anxiogenic –like effects and CRF antagonist reverse many behavioral responses to stress Alcohol is also powerful modulator of stress system- both acute and chronic intake of alcohol activate HPA axis and this results in CRF release in hypothalamus which activates stress response and extracellular levels of CRF increase in amygdale and bed of nucleus stria terminalis,CRF antagonist reverse these in experimental condition.

29. Neuropeptide Y (NPY) Neuropeptide Y (NPY) widely distributed in CNS but more in extended amygdale –may have role. In contrast CRF –in withdrawal NPY decreases and is parallel to increase CRF Thus not only neurotransmitters but also recruitment of CRF brain stress system and dysfunction of NPY brain antistress system

30. The models in this stage are based on conditioned reinforcement and stress. Environmental cues repeatedly paired with primary reinforces can acquire reinforcing properties via classical conditioning processes In this stage - 2 factors combine to produce strong motivation for drug seeking that leads to relapse A reactivation of the neurotransmitter system implicated in acute reinforcing effects of alcohol ( craving type 1) And residual deficits in reward function associated with protracted abstinence (craving type 2) Driving these neurochemical changes structuring of functional activity in prefrontal cortex and basolateral amygdala that facilitates cue-induced craving via glutamatergic,dopaminergic and opioid peptide activation .in contrast stress-induced reinstatement depends on CRF in extended amygdala . superimpose basal hypo activity in prefrontal cortex and dysregulation in extended amygdale reward system on craving circuit and one has powerful driving force for relapse to excessive alcohol consumption. Preoccupation/anticipation (craving ) stage of addiction cycle :

31. Experience Transmitter/Receptor euphoria/pleasure Dopamine, Opioids anxiolysis /ataxia  GABA sedation/amnesia  GABA +  NMDA nausea 5HT 3 neuroadaptation NMDA, 5HT stress CRF withdrawal GABA, NMDA ( Ca, Mg) memory NMDA Craving and relapse NMDA

32. 3.Mech of Relapse 1.Cue related OFC, VTA & N.Acc Glutamate DA 2.Stress related Lateral & Ventral TA N.Adr, DA,CRF 3.Drug related VTA & N.Acc DA Glutamate Addiction & its neurobiology

33. Reducing Relapse: Future directions.

34. THANK YOU